Vascular reactive oxygen species (ROS) are known to be involved in atherosclerosis development and progression. NADPH oxidase 4 (Nox4) is a constitutively active ROS-producing enzyme that is highly expressed in the vascular endothelium. Nox4 is unique in its biology and has been implicated in vascular repair, however, the role of Nox4 in atherosclerosis is unknown. Therefore, to determine the effect of endothelial Nox4 on development of atherosclerosis, Apoe E−/− mice +/− endothelial Nox4 (ApoE−/−+EC Nox4) were fed a high cholesterol/high fat (Western) diet for 24 weeks. Significantly fewer atherosclerotic lesions were observed in the ApoE−/− + EC Nox4 mice as compared to the ApoE−/− littermates, which was most striking in the abdominal region of the aorta. In addition, markers of T cell populations were markedly different between the groups; T regulatory cell marker (FoxP3) was increased whereas T effector cell marker (T-bet) was decreased in aorta from ApoE−/− + EC Nox4 mice compared to ApoE−/− alone. We also observed decreased monokine induced by gamma interferon (MIG; CXCL9), a cytokine known to recruit and activate T cells, in plasma and tissue from ApoE−/− + EC Nox4 mice. To further investigate the link between endothelial Nox4 and MIG expression, we utilized cultured endothelial cells from our EC Nox4 transgenic mice and human cells with adenoviral overexpression of Nox4. In these cultured cells, upregulation of Nox4 attenuated endothelial cell MIG expression in response to interferon-gamma. Together these data suggest that endothelial Nox4 expression reduces MIG production and promotes a T cell distribution that favors repair over inflammation, leading to protection from atherosclerosis.

Mixed lineage kinases, or MLKs, are members of the MAP kinase kinase kinase (MAP3K) family, which were originally identified among the activators of the major stress-dependent mitogen activated protein kinases (MAPKs), JNK and p38. During stress, the activation of JNK and p38 kinases targets several essential downstream substrates that react in a specific manner to the unique stressor and thus determine the fate of the cell in response to a particular challenge. Recently, the MLK family was identified as a specific modulator of JNK and p38 signaling in metabolic syndrome. Moreover, the MLK family of kinases appears to be involved in a very wide spectrum of disorders. This review discusses the newly identified functions of MLKs in multiple diseases including metabolic disorders, inflammation, cancer, and neurological diseases.

Whole blood lactate concentration is widely used in shock states to assess perfusion. We aimed to determine if the change in plasma renin concentration over time would be superior to the change in lactate concentration for predicting in-hospital mortality in hypotensive patients on vasopressors.

Metabolic stress sensors like AMP-activated protein kinase (AMPK) are known to confer stress adaptation and promote longevity in lower organisms. This study demonstrates that activating the metabolic stress sensor AMP-activated protein kinase (AMPK) in endothelial cells helps maintain normal cellular function by promoting mitochondrial biogenesis and stress adaptation. To better define the mechanisms whereby AMPK promotes endothelial stress resistance, we used 5-aminoimidazole-4-carboxamide riboside (AICAR) to chronically activate AMPK and observed stimulation of mitochondrial biogenesis in wild type mouse endothelium, but not in endothelium from endothelial nitric oxide synthase knockout (eNOS-null) mice. Interestingly, AICAR-enhanced mitochondrial biogenesis was blocked by pretreatment with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin. Further, AICAR stimulated mTORC1 as determined by phosphorylation of its known downstream effectors in wild type, but not eNOS-null, endothelial cells. Together these data indicate that eNOS is needed to couple AMPK activation to mTORC1 and thus promote mitochondrial biogenesis and stress adaptation in the endothelium. These data suggest a novel mechanism for mTORC1 activation that is significant for investigations in vascular dysfunction.

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Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1/Creb1. JNK3 acts through Forkhead box O3 (Foxo3a) to suppress the activity of Egr1/Creb1 transcription regulators in vitro. In JNK3-deficient cells, Foxo3a is suppressed which leads to Egr1/Creb1 activation and upregulation of downstream growth factors. Collectively, these data suggest that the JNK3-Foxo3a-Egr1/Creb1 axis coordinates the vascular remodeling response in peripheral ischemia.

We present a series of kidney transplant dysfunction secondary to lower extremity deep venous thrombosis (DVT). A 70-year-old man underwent living unrelated kidney transplantation and presented 2 months postoperatively with acute kidney injury (AKI) secondary to external iliac vein thrombosis. Graft function improved after endovascular intervention. A 43-year-old man underwent living unrelated kidney transplantation and presented 3 years postoperatively with AKI secondary to external iliac vein thrombosis. Graft function recovered after thrombolysis. A 42-year-old woman underwent simultaneous pancreas and kidney transplantation. Four weeks postoperatively, she had AKI secondary to common femoral vein DVT. Her graft function improved after common iliac vein stenting. A 67-year-old man underwent living unrelated kidney transplantation and presented a week later with lower extremity DVT and AKI. His graft function improved with anticoagulation. Iliofemoral DVT can cause allograft dysfunction. The cause may be multifactorial. Endovascular intervention is safe and feasible when anticoagulation fails.

Study Design. This was an observational cohort study of patients receiving multilevel thoracic and lumbar spine surgery. Objective. The aim of this study was to identify which patients are at high risk for allogeneic transfusion which may allow for better preoperative planning and employment of specific blood management strategies. Summary of Background Data. Multilevel posterior spine surgery is associated with a significant risk for major blood loss, and allogeneic blood transfusion is common in spine surgery. Methods. A univariate logistic regression model was used to identify variables that were significantly associated with intraoperative allogeneic transfusion. A multivariate forward stepwise logistic regression model was then used to measure the adjusted association of these variables with intraoperative transfusion. Results. Multilevel thoracic and lumbar spine surgery was performed in 921 patients. When stratifying patients by preoperative platelet count, patients with pre-operative thrombocytopenia and severe thrombocytopenia had a significantly higher rate of transfusion than those who were not thrombocytopenic. Furthermore, those with severe thrombocytopenia had a higher rate of red blood cells, fresh frozen plasma, and platelet transfusion than those with higher platelet counts. Multivariate logistic regression found that preoperative platelet count was the most significant contributor to transfusion, with a platelet count ≤100 having an adjusted odds ratio (OR) of transfusion of 4.88 (95% confidence interval [CI] 1.58–15.02, P = 0.006). Similarly, a platelet count between 101and 150 also doubled the risk of transfusion with an adjusted OR of 2.02 (95% CI 1.01–4.04, P = 0.047). The American Society of Anesthesiologists classification score increased the OR of transfusion by 2.5 times (OR = 2.52, 95% CI 1.54–4.13), whereas preoperative prothrombin time and age minimally increased the risk. Conclusion. Preoperative thrombocytopenia significantly contributes to intraoperative transfusion in multilevel thoracic lumbar spine surgery. Identifying factors that may increase the risk for transfusion could be of great benefit in better preoperative counseling of patients and in reducing overall cost and postoperative complications by implementing strategies and techniques to reduce blood loss and blood transfusions. Level of Evidence: 2